TIL - Tumor infiltrating lymphocytes

I haven't put up a great deal about TIL therapy.  It is a complicated and somewhat risky process.  Selection if often very exclusive...partly because it can be a very tough treatment....and partly due to (in my mind) the desire for some of the institutions who provide it to skew their results into a more impressive report through selection of the 'best' candidates. 
But, again for dear Josh (and the rest of you in need) I am putting together some information as best I can.  Here we go....

In this post from 2013:  Ode to Pati  I said.......

"What is TIL?  TIL (Tumor infiltrating lymphocytes) are used in an ACT (adoptive cell transfer) therapy like this:  A tumor is removed from the patient's body.  Lymphocytes are collected from it.  Those lymphocytes are tested in order to identify the cells that show the greatest anti-tumor activity.  Then....those particular cells are grown in a lab for several weeks.  If the TIL cells grow sufficiently, the patient is given a body pounding dosing of chemotherapy to rid the body of other lymphocytes so that the new TIL batch will be accepted more readily when they are infused with no other immune cells there to attack them.  The newly grown lymphocytes are then returned to the patient in an infusion along with a cytokine (immune stimulating agent) like IL2 (interleukin 2).  In numerous studies TIL demonstrates a 50% response rate in patients with metastatic melanoma."

So....basically.  A tumor is harvested.  T-cells are extracted from it...with the idea that they were good soldiers who had already recognized and were in the process of attacking that tumor.  To increase their numbers...they are grown in a dish.  To further their interests...the patient (ie the battlefield) is injected with bad stuff (IL-2, IL-21, or cyclophosphomide and fludarabine, are frequently used) to kill off T-cells that might try to block their fight with the tumor...and/or support the good T-cells...which are then sent back into battle (ie injected into the patient)!

Here's the Wiki version...which is pretty good:  wiki: Adoptive cell transfer

Here is a recent post about a new TIL study that is recruiting:  TIL: tumor infiltrating lymphocytes

Now....the nifty thing that is happening in TIL therapy today....is that researchers are genetically modifying the t-cells they harvest from the tumor to make them even better at recognizing, attacking, and killing the tumors in question.  There are several different ways they are doing this and it is all rather complicated...but super cool.

In the study being considered:  Transfer of genetically engineered lymphocytes in melanoma patients
Here's the deal: This trial was started in 2012.  There are 4 cohorts with 4 dosing levels.  Not sure where they are in that process at this moment.   You get one infusion of TIL with low dose IL2.  You have to be "positive for both tyrosinase and HLA-A2" per biopsy and pass their heart test.  If you've had ipi, you have to be 3 months post last dose.  If BRAF positive you have to have failed Vemurafenib or been offered Vemurafenib and declined. This exclusion is present:  "Patients that have undergone immunotherapy in combination with non-myeloablative chemotherapy." Various lab values have to be in normal ranges.  It is offered at Loyola.

Here is an old report from 2006:  Cancer regression in patients after transfer of genetically engineered lymphocytes.  It notes that of 15 patients treated at that point, 2 durable response were attained.  Generally 50% of TIL patients gain a durable response...remembering we are talking about a select group.  At the end of the article (which is available as a PDF file) it says:  "In human subjects, normal autologous T lymphocytes, transduced ex vivo with anti-TAA–TCR genes and reinfused in cancer patients, can persist and express the transgene for a prolonged  time in vivo and mediate the durable regression of large established tumors. Although the response rate (2 out of 15 patients or 13%) seen in cohorts 2 and 3 is lower than that achieved by the infusion of autologous TILs (50%), this method has potential for use in patients for whom TILs are not available."

A complicated bunch of mess....but there you go. - c

CAVATAK - intralesional therapy derived from the coxsackievirus

Many intralesional therapies, medicine that is injected directly into a tumor, have been found to have some success in melanoma.  We have learned that, at times, they can not only kill the tumor into which they are injected, but "by-stander" tumors as well. First tried in 1975 with the BCG vaccine, things as disparate as IL2, Allovectin-7 (a DNA mixture), T-VEC/OncoVEX (derived from the herpes virus), L19, PV-10 (from the dye Rose Bengal), GM-CSF, and CAVATAK (derived from the coxsackievirus) have been used.  Additionally, some of these intralesionals have been tested combined with systemic immunotherapy.  The idea being that one could prime an immune response by injecting a tumor with an oncolytic virus, eliciting a T-cell influx, and follow with systemic immunotherapy.

Here's some background on the process:  Intralesional therapy for melanoma
Here is a brief review as well as reports from a study where T-VEC was combined with pembro, another with T-VEC and ipi, ipi given with IL2, as well as a report from the CALM study [don't you love their names????!!!] in which the coxsackievirus (CAVATAK) was administered singly:  From ASCO 2015: intralesional therapy for melanoma
Here's specifics on T-VEC:   Good News - local and systemic response to T-VEC
Here's the low-down on PV-10:  ASCO 2014: Rose Bengal (PV-10) with additional links
T-VEC combined with ipi: Pick your poison: Weber and Agarwala
     "When ipi is combined with T-VEC (an intralesional therapy) you get a better response rate...about 55% combined complete and partial responses....than with either drug alone."

Now....in truth....I am putting this together for my dear friend, Josh....so I am going to focus on an option he is looking at....CAVATAK with ipi.

Here is info from the CAVATAK only, CALM trial:

 Final data from CALM: A phase II study of Coxsackievirus A21 (CVA21) oncolytic virus immunotherapy in patients with advanced melanoma.  ASCO - J Clin Oncol 33, 2015.  Andtbacka, Curti, Kaufman, Daniels, et al.

"CVA21 is a novel bio-selected oncolytic and immunotherapeutic strain of Coxsackievirus A21.  Intratumal injection initiates preferential tumor cell infection, cell lysis [death] and enhancement of a systemic anti-tumor immune response.  The CALM study looked at 57 patients with treated or untreated, unresectable Stage IIIC-IV melanoma.  Patients were given injections on study days 1, 3, 5, 8, and 22, then every 3 weeks for a further 6 injections.  Patients showing immune-related progression-free survival or better at 6 months were eligible for 9 additional injections.  RESULTS:  21 of 57 (38%) patients displayed progression free survival at 6 months with median PFS of 4.2 months.  Overall response rate was 28% (16 of 57) with a more than 6 month durable response rate of 19% (11 of 57).  Median time to response was 2.8 months, 1 year survival rate was 75% (43 of 57 patients).  At more than 16 months, median duration of response in responders and median overall survival for all patients was not yet reached.  Most common side effects = Grade 1 fatigue, chills, local injection site reaction, and fever.  No grade 3 or 4 reactions.  Further studies with CVA21 in combination with other immunotherapies are in process."

And this link/synopsis of Weber's "What's new in 2016" talk...discusses what's coming and recent in melanoma care as well as CALM results:  Immunology update webinar for melanoma
Within...this blurb is included:  

Intralesional Immunotherapy With Oncolytic Coxsackievirus A21 (CVA21) 
 Final response and safety data of the open-label, multicenter phaseII CALM (CAVATAK in Late-stageMelanoma) study of intratumoral CVA21 in 57 patients with unresectable stage IIIC/IV melanoma.    The study met its primary endpoint.  22 of 57 (38.6%) evaluable patients with PFS at 6 months.    Median PFS of 4.2 mos.   ORR 28.1%; median TTR 2.8 mos.  1-year survival rate 75.4%.  Median OS and median DOR not reached (16.5 mos follow-up).  Most common AEs were grade 1 fatigue, chills, fever, and injection site reactions; no grade 3/4 AEs observed.  Looks like another promising intralesional therapy.  Will soon have phase 3 study.

A link to one other report:   Viralytics reports positive final results from cavatak phase 2 melanoma trial

Here is a link to:  Intratumoral CAVATAK and ipi trial
Apparently folks will get ipi at 3mg/kg 4 times.  You have to have an injectable tumor (per their criteria) and CAVATAK will be injected 4 specific times and then every three weeks for up to one year.  The study is a Phase 1 trial, sponsored by Viralytics and was started in late 2014. You can't have taken ipi for metastatic melanoma, but you can have taken it as an adjuvant as long as you did not experience a grade 3 toxicity.  Trial is recruiting in California, Oregon and Illinois.

CAVATAK is also being studied in bladder cancer and non-small-cell lung cancer.  There is also a study combining CAVATAK with pembro for melanoma.  Here's the link:  Intratumoral cavatak and pembro trial  Here folks will get CAVATAK injections at specific times up to 19 total injections into "at least one cutaneous, subcutaneous tumor or palpable lymph node amenable to intratumoral injection" and pembro infusions every 3 weeks up to 2 years. Exclusions include:  no corticosteriods, ocular or mucosal melanoma.  No prior anti-PD1 or PDL1.  Also sponsored by Viralytics, recruiting in New Jersey.

Guess that's about all I got.  I have always been a fan of intralesional therapy...telling B that if I ever recur...and have to have some sort of surgery...I was going to beg to have Rose Bengal and lord knows what else...just splashed around in there before they sew me up.  Those who know B can imagine the big blue eye roll that comment gets me....but there you go!!!  Love you, Josh!  - c

Happy.....

....to all the moms...there through thick and thin, the fabulous and the trying.  Though in truth, my chickadees have given far more to me than I to them.  Love my critters!!! - mommy

Sew Chaotically! - A pinkie pink power girl sun dress!!!

When Rosie was little...she wouldn't be a power woman....that was too mundane.  She was a pinkie pink power girl!!!  Which evolved into:  Pinky Pink Power Women

and the...Perky Peptide Patient with her Perky Peptide Posse!! Back in 2011, y'all!!!  This shot was from a stop at Ga Tech to visit Roo after Nivo and peptide injections in Tampa!!!  Wow!  Those were the days! 

But now...pink is pretty and older and even more fabulous!  Just like Roo...so for her birthday....  There was this:

Ancient pattern that I had and made for myself when I was Roo's age!!!  (Mine was blue...shocking, I know!)

I fully lined hers....since the fabric is a very delicate gingham.

Ta dah!

 

 

I'm happy to say it fit her perfectly!!!!  Happy, happy day my pinkie, pink power girl!!!!!  I love you! mommy

In melanoma care....we've come a long way baby!!!

Real-world treatment practice in patients with advanced melanoma in the era before ipilimuab:  results from the IMAGE study.  Middleton, Dalle, Claveau, et al.  Cancer Med 2016 4/26. 

The therapeutic landscape for advanced melanoma has recently been transformed by several novel agents (immune checkpoint inhibitors and molecular-targeted agents). The prospective, multi-site, observational study IMAGE (ipilimumab: management of advanced melanoma in real practice) included a retrospective cohort to describe real-world treatment prior to approval of the immune checkpoint inhibitor ipilimumab. This retrospective cohort of patients, who started second-line/subsequent treatment for advanced melanoma within 3 years before ipilimumab approval, was selected randomly by chart review. Collected data included treatment history, patient outcomes, and healthcare resource utilization. All patients had ≥1 year of follow-up data. This analysis included 177 patients from Europe (69%) and North America (31%). The most common index therapies (used alone or in combination) were fotemustine (23%), d
acarbazine (21%), temozolomide (14%), and platinum-based chemotherapy (14%). Most patients (89%) discontinued treatment during the study period; the most common reason was disease progression (59%). Among patients with tumor assessment (153/177; 86%), 2% had complete response, 5% had partial response, and 12% had stable disease on last tumor assessment. At 1-year study follow-up, median progression-free survival was 2.6 months and median overall survival was 8.8 months. During follow-up, 95% of the patients had healthcare visits for advanced melanoma, 74% of whom were hospitalized or admitted to a hospice facility. These results provide insights into patient care with advanced melanoma in the era before ipilimumab and may serve as a benchmark for new agents in future real-world studies.

So this was 177 folks being treated from 2008 - 2010....not that long ago.....before ipi, BRAFi and anti-PD1 were FDA approved.  And "at 1-year study follow-up, median progression-free survival was 2.6 months and median overall survival was 8.8 months."   While in this study:  Pembro/keytruda's overall response  Pembro provided a "12-month progression-free survival rate of 35%, and median overall survival of 23 months."  And here:  Nivolumab/Opdivo shows impressive OS  "the median OS was 20.3 months, the 5-year OS rate was 35.3% and the 30-month PFS rate was 25.7%."  We know the benefits BRAFi can provide...if only short term....but with some adjustments others are reaping their benefits and managing side effects for years.  Additionally, work continues to be done by researchers and ratties in the area of immunotherapy combo's, IDO inhibitors, LAG3, CDK4/6 inhibitors, various meds/treatments that prevent tumor resistance to BRAFi, DNA pcr and tumor testing that may help determine who will respond to what treatment....

But...it is not enough....not nearly enough.  Holding many of my amazing peeps in my heart today....Dfeng, Charlie S, Josh, John and so many others....hang in there guys....hang in there. love, c

Combining alternative and conventional treatments for melanoma....a risky business!

Mother Nature is a tricky B!!!!  She can give us rains that provide our water supply and make crops grow one minute followed by torrential floods that kill and wipe out cities the next. All that is found in nature is not benign.  In the plant world, poison ivy and hemlock come to mind.  Yet we are lucky to have Vincristine, derived from the periwinkle and categorized as an essential medication by the WHO, for the wonderful cures it can provide folks suffering from leukemia, Hodgkin's disease and other cancers.  Morphine, aspirin, digitoxin, quinine, and Paclitaxel are just a few of the drugs derived from plants that have benefited humans across the globe.  Then again, we have the beauty of tics and mosquitoes along with the germs they carry from the natural world. Speaking of the littlest beings - viruses and bacteria - while they can damage the unborn, bring illness, suffering and even death - alternatively, they also allow us the enjoyment of cheese, beer and wine and the incredible life saving properties of penicillin.  All this is merely a reflection of the pros and cons of the "natural/alternative" world.  Because there is also this: 

Risk of interactions between complementary and alternative medicine and medication for comorbidities in patients with melanoma.  Loquai, Dechent, Garzarolli et al.  Med Oncol. 2016 May.  

Complementary and alternative medicine (CAM) is used widely among cancer patients. Beside the risk of interaction with cancer therapies, interactions with treatment for comorbidities are an underestimated problem. The aim of this study was to assess prevalence of interactions between CAM and drugs for comorbidities from a large CAM usage survey on melanoma patients and to classify herb-drug interactions with regard to their potential to harm. Consecutive melanoma outpatients of seven skin cancer centers were asked to complete a standardized CAM questionnaire including questions to their CAM use and their taken medication for comorbidities and cancer. Each combination of conventional drugs and complementary substances was evaluated for their potential of interaction. 1089 questionnaires were eligible for evaluation. From these, 61.6 % of patients reported taking drugs regularly from which 34.4 % used biological-based CAM methods. Risk evaluation for interaction was possible for 180 CAM users who listed the names or substances they took for comorbidities. From those patients, we found 37.2 % at risk of interaction of their co-consumption of conventional and complementary drugs. Almost all patients using Chinese herbs were at risk (88.6 %). With a high rate of CAM usage at risk of interactions between CAM drugs and drugs taken for comorbidities, implementation of a regular assessment of CAM usage and drugs for comorbidities is mandatory in cancer care. 

Given the horrible tenacity and morbidity associated with melanoma, and the fact that some of the best treatments provide only a 40% response rate, it is sorely tempting to add a dab of this and a bit of that to our chosen medical treatment plan.  Adding things like NSAIDs (mentioned recently in the post:  Celecoxib (stuff that's in NSAIDs like aspirin and advil) works synergisticaly with anti-PD1) sounds like a no brainer, right?  And while an aspirin a day USUALLY causes no harm, there are those for whom it is NOT a good idea!  In fact, most medical researchers agree...if aspirin were put before the FDA today....it would likely be a prescription medication!!!  So...just remember:  all things over the counter and 'natural' are not always good for us.  Talk to your oncologist before adding ANYTHING to your cancer treatment plan.

Wishing you well! - c

Don't give up. Don't ever give up.

Some of what has been going on with me, some of what I've been trying to say to others with questions about their life...their cancer...their treatment choices ~ brought this beautiful man and his incredible life to my mind again...

Stuart Scott.  1965-2015.  Stuart Scott's ESPY Speech

"Our life's journey is about the people that touch us...  Don't give up.  Don't ever give up.  When you die, that does not mean that you lose to cancer.  You beat cancer by how you live, why you live, and in the manner in which you live. So live!  Live!!  Fight like hell!  And when you get too tired to fight, then lay down, and rest.  And let somebody else fight for you. This whole journey thing - is not a solo venture.  This is something that REQUIRES support.” ~Stuart Scott~

Life IS a journey.  With ALL the roads, and dead ends, and pit stops, and fabulous scenic routes included.  The good, the bad, the ugly.  Also the mundane, the funny, the sad. It is the joy of a job well done, the thought of things that one could do better.  It is shared experiences and quiet time alone.  

Recently, I've worked extra at the office.  I've repainted a window sill and back porch railing since the Sucky A$$ painter we hired to do it last year (that would be me!!!) didn't go to the trouble to sand things all the way down as they should have and allow plenty of time between the application of layers for things to dry fully.  This time, the painter (that would be me!!) put in a great deal more time and thorough sanding (due to an awesome assistant...B!) so the outcome should be better.

I have been enjoying my yard...both the beauty of the work put in last year (when I managed to propagate the midnight blue irises Trina gave me...to create my own Giverny with the Johnny White beauties I already had) and several years before (when B planted the peonies and Rosie worked to create the bed of roses and azaleas in the front of the house)....

I've been reading and doing laundry and sewing surprises and talking to friends and dealing with pollen and getting gas and hurting for those I know are feeling sad and writing and worrying about different kids I am taking care of and you know....just regular stuff.  I've also been dealing with considerable right hip pain for about 6 weeks.  Don't start yelling, "You should have told me!!!" (You peeps know who you are!! And I love you!!)  I have little patience for whiners...especially when the whiner is me.  It was pretty bad.  Waking me at night.  Causing a limp.  But....it IS getting better.  And, yes...bone mets went through my mind.  It could happen. It is part of the world I live in.  And, no...I didn't stop running, or working, or playing.  I considered my options...and decided I would give it a minute...then deal with whatever it turned out to be.  It wasn't muscular.  It wasn't sciatica.  It was probably arthritic in nature...either thanks to anti-PD1 or the fact that I will be 52 soon.  I'll take that!!!  It beats any of my alternatives.

And in that spirit...this is what B has been up to...  Clearing trees.  Building a box.  Hauling dirt....

It may not look like much just now.  But, soon wild flowers will be blooming all along the path.  Bitter Sweet will be climbing over the arbor.  Tomatoes, squash, beans, radishes (Oh Lord, he's trying them again!!!), and carrots will be harvested and enjoyed.  Or not....

That's the thing.  It will be as it will be.  That doesn't mean I don't care.  It doesn't mean that I'll stop trying.  Don't give up.   Don't ever give up!

Do what you love.  Make sure the peeps you love know that you do.  Do your very best.  Then sit down and KNOW that you lived!  love, c